FDA Warns of Celebrex Heart Risk

WASHINGTON — The Food and Drug Administration on Friday warned physicians to consider alternatives to the popular arthritis drug Celebrex because of new evidence that, like the similar drug Vioxx, removed from the market in September, it doubles the chances of heart attacks and strokes.

The federal agency said it may soon take other actions, including requiring stronger warnings, or even blocking the drug from sale. The statements call into question the future of the widely used class of painkilling drug called Cox-2 inhibitors.

The FDA warning came just hours after Celebrex manufacturer Pfizer Inc. issued a statement saying that a study of the drug's efficacy as a cancer treatment found evidence of increased cardiovascular risk.

The study's findings added to the growing concerns about the effectiveness of the FDA's system for assessing the risks of new drugs and for monitoring dangerous side effects in medications it had already approved.

"Right now we have a situation where the public is left wondering when the next shoe might drop when it comes to drug safety," said Sen. Charles E. Grassley (R-Iowa), who held hearings last month on the problems with Vioxx. "At this point, no one can say with confidence whether the worst drug safety problems are behind us or ahead of us."

But Dr. John Jenkins, director of the FDA's Office of New Drugs said discovery of the problems with Celebrex is a sign that the system is working.

"I don't see this as a failure of the system," Jenkins said. "This is how drug development, drug approval and post-market monitoring is done, not only in the United States, but in all countries that have a regulatory system."

Pfizer gave no indication that it would withdraw the drug.

Dr. Joseph Feczko, president of worldwide development for Pfizer, said in a statement that doctors "should factor this new information" and weigh it against the risks of other painkilling drugs.

But patient groups voiced concern about the continued use of Celebrex and related drugs.

The Arthritis Foundation issued a statement Friday urging caution in the use of any Cox-2 inhibitor, a class of drug that targets an enzyme that causes inflammation but ignores another that protects the stomach lining.

That position was bolstered Friday with the release of a letter from three physicians at the Vanderbilt University School of Medicine in Tennessee warning doctors against prescribing another widely used Cox-2 inhibitor, Bextra, "except in extraordinary circumstances."

The letter, which will be published in the Thursday edition of the New England Journal of Medicine, was released early because of Pfizer's Celebrex announcement.

The doctors said that previous findings of an increased risk for heart bypass patients taking Bextra, which is also made by Pfizer, were serious enough to call into question the drug's safety for other people.

"This is a doomed class of drugs," said Dr. Sidney Wolfe, director of health research for the consumer advocacy group Public Citizen. "They will be taken off the market. It's a matter of when, not whether."

Celebrex and other Cox-2 inhibitors were developed to be a stomach-friendly alternative to old line anti-inflammatory medicines such as aspirin, ibuprofen and naproxen. Taken long term, the older medicines can cause gastric problems such as ulcerations and internal bleeding.

The new Cox-2 inhibitors became tremendous money makers because they are used as maintenance drugs, taken on a daily basis by millions of people worldwide. They sell for as much as $3 a pill. The older medicines sell for pennies a pill in generic versions sold in supermarkets and drug stores.

Celebrex and Bextra were expected to account for $5 billion of Pfizer's estimated 2005 sales of $55 billion, said Sena Lund a market analyst for Cathay Financial in New York. Roughly 27 million patients have taken Celebrex, according to Pfizer.

But in September, a serious problem emerged with one of the Cox-2 inhibitors. Merck & Co. pulled Vioxx off the market after it was found to cause heart attacks in some patients.

Vioxx doubled the risk of heart attacks, although the actual number of cases was very small.

Some researchers suspected that Cox-2 inhibitors might be reducing the body's production of a protein that prevents blood platelets from clumping together, possibly leading to a stroke or heart attack.

A week after Vioxx was pulled from the market, a report and an editorial released by the New England Journal of Medicine suggested that Celebrex and Bextra might also be linked to heart risks. The cardiologist who led earlier studies called on the FDA to change its advice to patients and doctors to reflect the new safety concerns.

The latest Pfizer study, conducted by the National Cancer Institute, was designed to see whether high doses of the drug could prevent the formation of certain precancerous colon polyps.

Dr. Ernest T. Hawk of the institute said the study, which has been going on for nearly three years, involved 2,000 patients, divided into three groups. Some were given a placebo. Others were given 400 or 800 milligrams of Celebrex per day.

The usual dose for arthritis patients ranges from 100 to 200 milligrams daily for osteoarthritis to 200 to 400 milligrams daily for rheumatoid arthritis.

As concerns were being raised about Vioxx, the cancer institute brought in a team of cardiac experts to evaluate its Celebrex data.

They found six cases of such adverse effects in the placebo group, 15 cases in the lower dose Celebrex group and 20 cases in the higher dose group. The risk of adverse effects was 2.5 times greater in the lower dose group and 3.4 times greater in the higher dose group, Hawk said.

The cancer institute halted the Celebrex study, and the National Institutes of Health on Friday ordered a review of more than 40 studies involving Cox-2 inhibitors.

Pfizer, however, said the cancer study was out of step with other evidence showing that Celebrex was safe.

There is a "large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen," Feczko said in a statement.

Indeed, there was some confusion in the medical world over the study's findings.

Researchers who studied Vioxx said the FDA needed more information to reach a conclusion on Celebrex.

"I was caught by complete surprise," said Dr. Gurkirpal Singh at Standford Medical School. "Everything with Celebrex was pointing in the direction that it had a small cardio-protective effect."

Singh said he would be "very cautious" about prescribing Celebrex to patients, although he did not think there was enough information to pull the drug from the market.

Another researcher, Dr. Bruce Psaty of the University of Washington, said the latest problem reinforced criticisms that the FDA's drug review and approval process was flawed.

"This is one of the problems with not getting good safety data early in the approval process," Psaty said. "It is not good for patients, nor for the pharmaceutical industry."

The FDA had planned to convene an advisory committee in February to discuss problems and strategies with Cox-2 inhibitors. Now, the agency may have to act sooner.

On Friday, an influential House panel probing Vioxx added Celebrex to its investigation. The Energy and Commerce Committee sent a letter to Pfizer Chairman Hank McKinnell requesting extensive records on the drug's development, approval, marketing and use by patients.

Pfizer's disclosure Friday may also launch "a race to the courthouse," said Jonathan Zasloff, a UCLA law professor.

There are already attorneys looking for Celebrex takers who have had heart attacks in an effort to put together a class-action lawsuit against Pfizer.

"But it's going to be a tricky case to win at trial," Zasloff said. "Lots of people have heart attacks whether or not they are taking Celebrex."

The attorneys also will have to find evidence that Pfizer knew there were risks prior to being notified of the cancer study.